The second issue is whether the current failure to find large genetic effects in endophenotypes can be read as a general indication of the complexity of genetic architecture for all phenotypes. Endophenotypes are assumed to have a relatively simple genetic architecture because there are relatively few pathways from gene to phenotype. The consequence is that sequence variants interact relatively directly with the phenotype so the correlation should be easier to detect. We have so far examined this assumption by investigating what is known about the genetic architecture of commonly investigated endophenotypes, and have shown that there is little evidence that it is considerably simpler than that of psychiatric disease. Perhaps we happen to have selected those phenotypes that have a complex genetic architecture. In the absence of detailed genetic analyses of multiple endophenotypes we cannot gainsay this point. However, we are able to approach this question from another point of view. We can ask what is known about the genetic architecture of phenotypes which have a much closer relationship to their genetic basis than endophenotypes for psychiatric disease.
